Background: Axl, a tyrosine kinase that with Tyro3 and Mer is a member of the TAM receptor family, regulates the inflammatory response to pathogens. TAM receptor-mediated signaling limits the TLR-induced production of proinflammatory cytokines through the involvement of the type I Interferon (IFN) receptor. Because IFN-a is a crucial regulator of DC functions, we investigated whether Axl expression is regulated by IFN-a and we analyzed the effects of the Axl ligand Gas6 (growth arrest-specific 6) on human DC. Materials and methods: DC were generated from monocytes in the presence of IFN-a (IFN/DC) or Interleukin-4 (IL-4/DC), and their expression of Axl, Tyro3, Mer, and Gas6 was investigated before or after the administration of maturation stimuli. In addition, we assessed Gas6 activity on DC survival and chemotaxis. Results: We show that Axl expression is induced by IFN-a during IFN/DC differentiation and that constitutively Axl-negative IL-4/DC express Axl following IFN-a-stimulation. This effect was inhibited by toll-like receptor (TLR)-dependent maturation stimuli such as lipopolysaccharide (LPS), polyinosinic : polycytidylic acid, TLR7/8 agonist and CD40L. LPS-induced Axl downregulation on the surface of IFN-a-treated DC correlated with an increased proteolytic cleavage of Axl and with elevated levels of its soluble form. GM6001, a general inhibitor of MMP (Matrix Metalloproteinase) and ADAM (A Disintegrin and Metalloproteinase) proteases, restored Axl levels on DC surface and diminished Axl shedding. Furthermore, the stimulation of Axl by Gas6 induced DC chemotaxis and rescued the cells from growth-factor deprivation-induced apoptosis. Conclusions: Our study provides evidence that Gas6/ Axl-mediated signalling regulates human DC activities, and identifies Gas6/Axl as a new pathway involved in DC chemotaxis.
Survival and migration of human dendritic cells are regulated by an interferon-alpha-inducible Axl/Gas6 pathway
SCUTERA, SARA AGATA CATERINA;GIOVARELLI, Mirella;MUSSO, Tiziana
2010-01-01
Abstract
Background: Axl, a tyrosine kinase that with Tyro3 and Mer is a member of the TAM receptor family, regulates the inflammatory response to pathogens. TAM receptor-mediated signaling limits the TLR-induced production of proinflammatory cytokines through the involvement of the type I Interferon (IFN) receptor. Because IFN-a is a crucial regulator of DC functions, we investigated whether Axl expression is regulated by IFN-a and we analyzed the effects of the Axl ligand Gas6 (growth arrest-specific 6) on human DC. Materials and methods: DC were generated from monocytes in the presence of IFN-a (IFN/DC) or Interleukin-4 (IL-4/DC), and their expression of Axl, Tyro3, Mer, and Gas6 was investigated before or after the administration of maturation stimuli. In addition, we assessed Gas6 activity on DC survival and chemotaxis. Results: We show that Axl expression is induced by IFN-a during IFN/DC differentiation and that constitutively Axl-negative IL-4/DC express Axl following IFN-a-stimulation. This effect was inhibited by toll-like receptor (TLR)-dependent maturation stimuli such as lipopolysaccharide (LPS), polyinosinic : polycytidylic acid, TLR7/8 agonist and CD40L. LPS-induced Axl downregulation on the surface of IFN-a-treated DC correlated with an increased proteolytic cleavage of Axl and with elevated levels of its soluble form. GM6001, a general inhibitor of MMP (Matrix Metalloproteinase) and ADAM (A Disintegrin and Metalloproteinase) proteases, restored Axl levels on DC surface and diminished Axl shedding. Furthermore, the stimulation of Axl by Gas6 induced DC chemotaxis and rescued the cells from growth-factor deprivation-induced apoptosis. Conclusions: Our study provides evidence that Gas6/ Axl-mediated signalling regulates human DC activities, and identifies Gas6/Axl as a new pathway involved in DC chemotaxis.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
